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Decarboxylative Thiolation of Redox-Active Esters to Free Thiols and Further Diversification ✉ Tianpeng Cao1, Tianxiao Xu1, Ruting Xu1, Xianli Shu1 & Saihu Liao 1,2

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Decarboxylative Thiolation of Redox-Active Esters to Free Thiols and Further Diversification ✉ Tianpeng Cao1, Tianxiao Xu1, Ruting Xu1, Xianli Shu1 & Saihu Liao 1,2 ARTICLE https://doi.org/10.1038/s41467-020-19195-w OPEN Decarboxylative thiolation of redox-active esters to free thiols and further diversification ✉ Tianpeng Cao1, Tianxiao Xu1, Ruting Xu1, Xianli Shu1 & Saihu Liao 1,2 Thiols are important precursors for the synthesis of a variety of pharmaceutically important sulfur-containing compounds. In view of the versatile reactivity of free thiols, here we report the development of a visible light-mediated direct decarboxylative thiolation reaction of alkyl 1234567890():,; redox-active esters to free thiols based on the abundant carboxylic acid feedstock. This transformation is applicable to various carboxylic acids, including primary, secondary, and tertiary acids as well as natural products and drugs, forging a general and facile access to free thiols with diverse structures. Moreover, the direct access to free thiols affords an advantage of rapid in situ diversification with high efficiency to other important thiol derivatives such as sulfide, disulfide, thiocyanide, thioselenide, etc. 1 Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), College of Chemistry, Fuzhou University, 350108 Fuzhou, China. 2 State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, 350108 Fuzhou, China. ✉ email: [email protected] NATURE COMMUNICATIONS | (2020) 11:5340 | https://doi.org/10.1038/s41467-020-19195-w | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19195-w he construction of molecule libraries with structural and A number of radical C–S bond formation reactions43–49 functional diversity is crucial for the study in the context have been reported, including the related decarboxylative trans- T 1–3 46–49 of chemical biology and drug discovery .Thiolsare formations pioneered by Barton in 1980s , but a direct radical important precursors for the synthesis of a variety of pharma- thiolation to free thiols remains elusive so far. The challenges for ceutically important sulfur-containing compounds, including the proposed radical decarboxylative thiolation to free thiols sulfonamides, sulfonyl fluorides, sulfoxides, sulfides, disulfides, probably lie in the labile nature of free thiols, which can lead to and so on, by virtue of their high reactivity and valence labile dimerization, undesired hydrogen transfer, and other side reac- nature, and widely employed in organic synthesis, polymer tions43. In fact, free thiols are commonly used as hydrogen atom preparation, materials science, and biomedicine4–17.Infact, transfer (HAT) catalysts or reagents in radical chemistry50–54, besides their well-known roles in protein structure stabiliza- and the HAT from a primary alkyl thiol to alkyl radicals is a fast tions18,19 and many enzymatic processes20,thiolisalsoone process (ca. 107 M−1s−1)52–54. Therefore, in the decarboxylative of the most targeted sites in post-translational protein mod- thiolation process, the desired thiol product (RSH) formed earlier ification (Fig. 1a)21–23. Inspired by the versatile reactivity of may intercept the newly generated alkyl radicals (R∙), thus leading thiols, we conceived that, based on the feedstock of abundant to the undesired alkane (R-H) formation (Fig. 1c). Nevertheless, carboxylic acid, a decarboxylative thiolation of acid-derived in radical polymerization, the chain-transfer agents (CTA) 24–39 * redox-active esters (RAEs) (RCO2A ) to free thiols could employed in reversible addition-fragmentation chain-transfer forge a novel access to various thiols and related derivatives polymerization can readily alter the radical addition rate by 8 −1 −1 with considerable structural diversity. In particular, the dec- adjusting the Z group and increase kadd to above 10 M s arboxylative access to free thiols could allow a further diversi- (Fig. 1, C, below)55,56, which inspired us to focus on the sulfur fication to other sulfur-containing compounds40–42 with a donor search in the beginning. Herein, we report our efforts in multiplied diversity by varying the coupling agents (e.g., with the successful identification of aryl thioamides as an effective various electrophiles E+,Fig.1b). sulfur donor, and the invention of visible light-mediated direct a Thiols in functionality transformation and protein modification SH SO2NH2 SO3R SO2F SH R SO2R SOR SCN SR SSR etc. Rpn13,PDB ID codes:6co4 SH as targeted site in protein modification b Diversity-oriented decarboxylative thiolation to free thiols (this work) CO H Activation CO A* Sulfur source S Diversification S 2 2 R H R E R R E+ • Abundant feedstock Decarboxylative thiolation • Various derivatives • Diverse structures • Multiplied diversity a b E+ Aa Ab A c CO H c 2 Thiolation SH ... S R R R E B a Bb B c ABC... Diversity ABC... Diversity Ca Cb Cc transfer multiplication Diverse ... ... ... Abundant Reactive thiol derivatives Compound library c Mechanistic consideration RSH 7 –1 –1 RH kHAT = ~10 M s Competing Well known (undesired) Decarboxylation CO2A* R R SET Sulfur donor? R SH Unknown (desired) S S kadd R S S R' Inspiration from RAFT: R + R' 6 8 –1 –1 kadd = 10 –10 M s Z k-add Z Chain transfer agent Fig. 1 Reaction design. a Thiols in functionality transformation and protein modification. b Diversity-oriented decarboxylative thiolation to free thiols. c Mechanistic consideration and the inspiration from reversible addition-fragmentation chain-transfer (RAFT) polymerization. 2 NATURE COMMUNICATIONS | (2020) 11:5340 | https://doi.org/10.1038/s41467-020-19195-w | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19195-w ARTICLE decarboxylative thiolation of alkyl RAEs to free thiols. Moreover, found beneficial and further increased the yield to 81% (entry 5 further diversification to other thiol derivatives, such as sulfide, vs. entry 6). The N-H group proved to be crucial for this disulfide, thiocyanide, and thioselenide via in situ trapping, is also transformation. Replacement with either one or two methyl demonstrated. groups (2g and 2h),bothresultedinasharpdropinyield (entries 7 and 8). Moreover, sulfur powder was also tested, but no desired thiol product was observed (entry 9). With 2f as the Results sulfur donor, we conducted a further reaction optimization, Reaction optimization. We commenced our study with the including search for sulfur donors suitable for the radical thiolation photocatalyst, solvent, light source, and so on (for details, reaction, by employing dihydrocinnamic acid-derived RAE (1) please see the Supplementary Tables 2 and 3). Other photo- as the model substrate and Eosin Y-Na2/diisopropylethylamine catalysts, such as Ru(bpy)3Cl2·6H2O and Ir(ppy)3, gave lower (DIPEA) as the photoredox catalytic system (Table 1). Initially, yields (entries 10–13), while Eosin Y was found equally efficient thiourea 2a, which is frequently used as a sulfur donor in the (entry 14). Running the reaction in CH CN could slightly nucleophilic substitution reactions of alkyl halides57,58,was 3 fi ′ enhanced the selectivity (entry 15). Without light or photo- examined rst in the reaction, but only the alkane product 3 catalyst, no reaction or a low yield was observed (entries 16 and was observed (entry 1), indicating the radical reactivity is 17). To our delight, the employment of two equivalents of sulfur substantially different from the polar substitution reactions. donor 2f could further suppress the undesired alkane formation Other thioureas like 2b and 2c were also examined, but neither and increase the yield of the desired thiol product to a decent level of them afforded the desired thiol product (entries 2 and 3). We of 88% in the end (entry 18). then turned our attention to other types of sulfur donor (for more details about the reaction development, please see the Supplementary Figs. 1–9andTable1). To our delight, ben- Substrate scope. With the optimized reaction conditions in zothioamide was found being a promising sulfur donor for this hand, we next examined the reaction scope with a variety of decarboxylative thiolation reaction, and the desired thiol 3 primary, secondary, and tertiary acid-derived RAEs (Fig. 2). could be obtained as the predominant product in 77% yield Some free thiols are volatile and thus isolated in their disulfide (entry 4). We then carried out several modifications on the form by in situ trapping with diphenyl disulfide. These results are phenyl group of benzothioamides (entries 4–6). Electron- also included in Fig. 2. In cases of primary acids (3–18), we could withdrawing group (-CF3, 2e) led to a decreased yield of 35%, see a good functional group tolerance. Br, Cl, ether, ester, and while the introduction of an electron-donating group (2f)was also a triple C–C bond are all compatible in the reaction, and the Table 1 Reaction optimizations for decarboxylative thiolation to free thiolsa. O Sulfur donor (1.0 eq) SH O Ph 3 photocatalyst, DIPEA (1.1 eq) N Ph O + DCM, Ar, r.t., 24 h H O Ph 3' 1 6 W Blue LEDs Selected examples of sulfur donor: H S S S N S NH2 HN NH H2N NH2 N H 2a 2b 2c 2d S S S S NH2 NH2 N N H F3C MeO MeO 2e 2f 2g 2h Entry Sulfur donor Yield (3/3′)b Entry Catalyst Yield (3/3′)b 1 2a 0/81 10 [Ru(bpy)3]Cl2·6H2O 71/28 2 2b 0/76 11 Ir(ppy)3 37/32 3 2c 0/79 12 Rhodamine B 76/28 4 2d 77/26 13 Fluorescein 71/36 5 2e 35/28 14 Eosin Y 81/23 d 6 2f 81/23 15 Eosin Y-Na2 83/18 d,e 7 2g 2/72 16 Eosin Y-Na2 0/0 d,f 8 2h 3/97 17 w/o Eosin Y-Na2 38/10 c d,g 9 Sulfur powder 0/0 18 Eosin Y-Na2 88/6 aReaction conditions: 0.05 mmol scale, catalyst (2.5 mol%). Left entries: with Eosin Y-Na2 as the photocatalyst.
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